It is known that a selective subtype of excitatory amino acid receptors activated by N-methyl-D-aspartate (NMDA), Glutamate (GLU), and Aspartate (ASP) and competitively inhibited by 2-amino-5-phosphonovaleric acid (APV) are responsible for long term potentiation (LTP). Long term potentiation is defined as the increase in strength of synaptic transmission with repetitive use. LTP has been recognized as one type of synaptic plasticity and is believed to underlie behaviorally significant forms of memory storage and learning. The dysfunctions of excitatory amino acid receptors have been implicated in, e.g., the etiology of senile dementia of the Alzheimer type (SDAT), a disease characterized by severe memory loss, personality changes and symptoms of cortical disconnection; apraxias; asphasias; and agnosias. Glutamate receptors, particularly the NMDA subtype, have been shown to decrease in the neocortex of SDAT patients. The function of this receptor can also be allosterically inhibited by phencyclidine (PCP) and other dissociative anaesthetics, blocking LTP and resulting in learning and memory impairments.
The development of pharmacological agents with the ability to modulate the NMDA receptor in a positive manner has dual importance. In terms of basic neuroscience research it provides the necessary tools for the study of excitatory amino acid receptors, allowing discrimination of the actions of the NMDA receptor subtype from other glutamate receptors. In terms of clinical usefulness, such agents would be useful in treating memory and learning disorders, such as SDAT. The compounds are also effective as therapeutic agents in treating PCP toxicity and abuse.